This invention provides an improved process for preparing intermediates useful in the preparation of tricyclic compounds that are antihistamines. In particular, the compounds of this invention are useful in the preparation of antihistamines such as those disclosed in U.S. Pat. Nos. 4,282,233 and 5,151,423, especially loratadine and azatadine.
PCT Publication No. WO98/42676, published Oct. 1, 1998, discloses the following process for preparing tricyclic intermediates: 
wherein R, R1, R2, R3 and R4 are independently selected from hydrogen or halo, R5 and R6 are independently selected from hydrogen, alkyl, aryl or heteroaryl, wherein R5 and R6 are not both hydrogen, and R7 is Cl or Br. This process has some undesirable aspects, including the fact that carbon monoxide, a poisonous gas, must be used under high pressure to prepare the amide compound 2, and the fact that an expensive palladium catalyst must be used. The present invention provides an efficient process for preparing the tricyclic ketone that avoids these undesirable aspects.
This invention provides a process for preparing a compound having the formula 
comprising:
(a) reacting a compound having the formula 
with an isocyanate having the formula R1NCO to produce a compound having the formula 
(b) optionally hydrolyzing the compound of formula (III) to form an amide having the formula 
(c) reacting the compound of formula (III) or the amide of formula (IV) with a compound having the formula 
in the presence of a strong base to produce a compound having the formula 
and
(d) cyclizing the compound of formula (VI) to obtain the compound of formula (I), wherein R is H or Cl; M is selected from the group consisting of Li, Na, K, MgX, ZnRA, and Al(RA)2; RA is alkyl; X is halo; R1 is selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; and L is a leaving group.
This invention further provides a process for preparing a compound having the formula 
comprising reacting a compound having the formula 
with CO2 and a protonating agent to obtain the compound of formula (VIII), wherein M is selected from the group consisting of Li, Na, K, MgX, ZnRA, and Al(RA)2, wherein RA is alkyl and X is halo.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched hydrocarbon chains of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, optionally substituted by one or more substituents selected from C1 to C6 alkoxy, halo, or CF3.
xe2x80x9cAlkoxyxe2x80x9d means a group having the formula xe2x80x94Oxe2x80x94alkyl.
xe2x80x9cHaloxe2x80x9d refers to fluorine, chlorine, bromine or iodine radicals.
xe2x80x9cArylxe2x80x9d means phenyl or a polyaromatic ring (e.g., napthyl) optionally substituted by one or more substituents selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkoxy, halo, or CF3.
xe2x80x9cAralkylxe2x80x9d means a group having the formula xe2x80x94R-aryl, wherein R is alkyl;
xe2x80x9cHeteroarylxe2x80x9d means a 5- or 6-membered aromatic ring having one or two nitrogen atoms (e.g., pyridyl, pyrimidyl, imidazolyl or pyrrolyl), optionally substituted by one or more substituents selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkoxy, halo, or CF3;
xe2x80x9cHeteroaralkylxe2x80x9d means a group having the formula xe2x80x94R-heteroaryl, wherein R is alkyl;
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic carbocyclic ring of from 3 to 6 carbon atoms, optionally substituted by one or more substituents selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkoxy, halo, or CF3;
xe2x80x9cCycloalkylalkylxe2x80x9d means a group having the formula xe2x80x94R-cycloalkyl, wherein R is alkyl;
xe2x80x9cHeterocycloalkylxe2x80x9d means a 3 to 6 membered non-aromatic ring having from 1 to 3 heteroatoms selected from O, S and N, wherein the remaining members of the ring are carbon atoms, optionally substituted by one or more substituents selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkoxy, halo, or CF3;
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a group having the formula xe2x80x94R-heterocycloalkyl, wherein R is alkyl.
R is preferably Cl.
M is preferably selected from Li, Na, K, and MgX.
R1 is preferably alkyl or aryl. R1 is most preferably t-butyl, phenyl or 4-chlorophenyl.
Examples of suitable leaving groups, L, include, but are not limited to Cl, Br, I, alkyl sulfonates, aryl sulfonates, dialkyl phosphates, diaryl phosphates and RBOC(O)Oxe2x80x94, wherein RB is alkyl or aryl. L is preferably selected from Cl, Br, mesylate, tosylate, brosylate, triflate, and xe2x80x94OP(OC2H5)2.
Certain substituents, solvents and reagents are referred to herein by the following abbreviations: lithium diisopropylamide (LDA); n-butyl lithium (n-BuLi); tetrahydrofuran (THF); and phenyl (Ph).
The compounds of formula (I) prepared by the present process are useful as intermediates in the procedures described in U.S. Pat. No. 5,151,423 to obtain the desired compounds wherein the piperidinyl ring is N-substituted. Using those procedures, the compounds of formula (I) may be reacted with a substituted piperidine of the formula 
wherein L1 is Cl or Br, to obtain a compound of the formula 
This compound is converted to the corresponding piperidylidene, the nitrogen is deprotected, and the compound is reduced to the piperidyl form. The piperidinyl nitrogen can then be reacted with a variety of compounds, e.g., an acyl compound such as an ester or acyl chloride to form the desired amide.
The compound of formula (VIII) produced in accordance with our invention can be used to prepare the amide of formula (IV) by reacting it with an organic base, e.g., triethylamine, followed by an acid chloride, e.g., pivaloyl chloride or a chloroformate, e.g., C2H5OCOCl in a suitable solvent such as dichloromethane at a temperature of about xe2x88x9230xc2x0 C. to 0xc2x0 C. to give a mixed anhydride, and reacting the mixed ahydride with an amine of the formula NH2R1 at a temperature of xe2x88x9230xc2x0 C. to 0xc2x0 C. to form the amide of formula (IV).
Those skilled in the art will recognize that the compound represented by formula (III) exhibits resonance as shown below: 
As used herein, the compound of formula (III) is intended to represent both of these resonance structures, as well as the resonance hybrid of these structures.
The starting compounds of formula (II) are either known in the art, or can be readily prepared by one skilled in the art, using conventional methods. Preferably, the starting compounds of formula (II) are prepared in situ from a 2-halo 3-methyl pyridine, e.g., 2-bromo 3-methyl pyridine. For example, when M is Li, Na, or K, the compound of formula (II) can be prepared by reacting 2-bromo 3-methyl pyridine with an alkyl or aryl lithium, sodium or potassium compound, preferably an n-butyl lithium, sodium or potassium. When M is MgX, the compound of formula (II) can be prepared by reacting 2-bromo 3-methyl pyridine with an alkyl or aryl Grignard. When M is ZnRA or Al(RA)2, the compound of formula (II) can be prepared by reacting 2-bromo 3-methyl pyridine with Zn(RA)2 or Al(RA)3.
In step (a) of the present process, the compound of formula (II) is reacted with an isocyanate having the formula R1NCO to produce the compound of formula (III). Preferably, the amount of isocyanate used in step (a) is 1.0 to 2.0 equivalents, more preferably, 1.0 to 1.5 equivalents, most preferably 1.0 to 1.1 equivalents. The reaction of step (a) is preferably carried out in an organic solvent, more preferably an aprotic organic solvent. Examples of suitable solvents, include, but are not limited to THF, ethylene glycol dimethyl ether, diethyl ether, methyl t-butyl ether, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, and mixtures thereof. THF,N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, and mixtures of THF and ethylene glycol dimethyl ether are particularly preferred. Step (a) is preferably carried out at a temperature of xe2x88x92110 to xe2x88x9240xc2x0 C., more preferably xe2x88x9290 to xe2x88x9260xc2x0 C., most preferably xe2x88x9280 to xe2x88x9270xc2x0 C.
Optionally, the compound of formula (III) may be hydrolyzed to form the amide of formula (IV) (step (b)). The optional hydrolysis is preferably carried out by quenching the reaction mixture from step (a) with a saturated aqueous solution of ammonium chloride. Alternatively, dilute HCl or dilute sulfuric acid could be used instead of ammonium chloride. The hydrolysis is preferably carried out at a temperature of xe2x88x9220 to 20xc2x0 C., more preferably xe2x88x9210 to 10xc2x0 C., most preferably 0 to 5xc2x0 C.
In step (c), the compound of formula (III) or the amide of formula (IV) is reacted with the compound of formula (V) in the presence of a strong base to produce the compound of formula (VI). Examples of strong bases include, but are not limited to: butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilylamide, and sodium amide. The strong base is preferably butyl lithium or LDA. Preferably, the amount of strong base used in step (c) is 2.0 to 2.5 equivalents, more preferably, 2.0 to 2.2 equivalents, most preferably 2.0 to 2.05 equivalents. Preferably, the amount of compound (V) used in step (c) is 1.0 to 1.5 equivalents, more preferably, 1.0 to 1.2 equivalents, most preferably 1.0 to 1.1 equivalents. Step (c) is preferably carried out at a temperature of xe2x88x9280 to 20xc2x0 C., more preferably xe2x88x9260 to xe2x88x9210xc2x0 C., most preferably xe2x88x9240 to xe2x88x9230xc2x0 C.
In a particularly preferred embodiment, step (b) is not carried out, and the product produced in step (a) is not isolated prior to carrying out step (c), i.e., steps (a) and (c) are carried out as a one-pot process.
In step (d), the compound of formula (VI) is cyclized to obtain the compound of formula (I). The cyclization is preferably carried out in an organic solvent, preferably an aprotic organic solvent. The aprotic organic solvent is preferably selected from dichloroethane, methylene chloride, benzene, and halogenated aromatic solvents, e.g., chlorobenzene, dichlorobenzene, trichlorobenzene, and trifluoromethylbenzene.
Preferably, the cyclization is carried out by reacting the compound of formula (VI) with a dehydrating agent to produce an imine having the formula: 
and hydrolyzing the imine of formula (VII) to produce the compound of formula (I). The dehydrating agent is preferably selected from the group consisting of P2O5, P2O3, P2O3Cl4, POCl3, PCl3, PCl5, C6H5P(O)Cl2 (phenyl phosphonic dichloride), PBr3, PBr5, SOCl2, SOBr2, COCl2, H2SO4, super acids, and anhydrides of super acids. More preferably, the dehydrating agent is selected from P2O5, P2O3Cl4, PBr3, PCl5, POCl3, C6H5P(O)Cl2, (CF3SO2)2O, and (CF3CF2SO2)2O.
The reaction of compound (VI) with the dehydrating agent is preferably carried out at a temperature of 10 to 120xc2x0 C., more preferably, 15 to 90xc2x0 C., most preferably 20xc2x0 to 90xc2x0 C. The time for reaction ranges from 1 to 60 hours, preferably 2 to 40 hours, most preferably 5 to 35 hours.
It is particularly preferred to form the imine by contacting the reaction mixture of the compound of formula (VI) and the dehydrating agent with an additional agent selected from the group consisting of a Lewis acid or a super acid. Examples of Lewis acids include AlCl3, FeCl3, ZnCl2, AlBr3, ZnBr2, TiCl4, and SnCl4. Of the foregoing, AlCl3, FeCl3, ZnCl2, and ZnBr2 are particularly preferred. Examples of super acids include CF3SO3H, 
and HF/BF3. Of the foregoing super acids, CF3SO3H is particularly preferred. The contacting by the Lewis acid or the super acid may be accomplished by adding it prior to, contemporaneously with, or after the time at which the dehydrating agent is brought into contact with the compound of formula (VI). Particularly preferred combinations of dehydrating agents and Lewis acids or super acids include P2O5/CF3SO3H, PCl5/AlCl3, PCl5/FeCl3, POCl3/ZnCl2, and POCl3/ZnBr2.
When a dehydrating agent other than an anhydride is used, preferably the dehydrating agent is used in amounts ranging from 1.0 to 20 equivalents, more preferably, 1.0 to 10 equivalents, most preferably, 1.0 to 8.0 equivalents. When the dehydrating agent is an anhydride of a super acid, it is preferably used in amounts ranging from 0.5 to 10 equivalents, more preferably 1.0 to 5.0 equivalents, most preferably, 1.2 to 2.0 equivalents. When a Lewis acid is used in addition to the dehydrating agent, the Lewis acid is preferably used in amounts ranging from 1 to 20 equivalents, more preferably 1.5 to 10 equivalents, most preferably 2 to 5 equivalents. When a super acid is used in addition to the dehydrating agent, the super acid is preferably used in amounts ranging from 0.5 to 10 equivalents, more preferably, 1 to 5 equivalents, most preferably, 2 to 4 equivalents.
The imine of formula (VII) is preferably hydrolyzed by adding water, preferably in an amount ranging from 1 to 10 volumes relative to the amount of the compound of formula (VI) used, more preferably 1.5 to 7 volumes, most preferably 2 to 5 volumes. The hydrolysis is preferably carried out at a temperature of from 20 to 120xc2x0 C., more preferably from 30 to 100xc2x0 C., most preferably from 40 to 80xc2x0 C.
The process for converting the compound of formula (II) into the compound of formula (VIII) is carried out by reacting the compound of formula (II) with CO2 and a protonating agent to form the compound of formula (VIII). The reaction is preferably carried out at a temperature of xe2x88x92110 to 0xc2x0 C., more preferably xe2x88x9280 to xe2x88x9220xc2x0 C., most preferably xe2x88x9260 to xe2x88x9240xc2x0 C. The protonating agent is preferably water or an acid. Preferably, the CO2 is in the form of dry ice or as a gas. Preferably, the amount of CO2 used is 1 to 10 equivalents, more preferably, 1 to 5 equivalents, most preferably 1 to 2 equivalents. Most preferably, the compound of formula (II) is reacted with the CO2 in an organic solvent, and the reaction mixture is protonated by quenching it with water.
The isocyanate (R1NCO) and the compound of formula (V) used in the foregoing processes are either known compounds or can be readily prepared by one skilled in the art using known methods.
Those skilled in the art will appreciate that unless stated otherwise, the compounds produced in the various process steps can, if desired, be separated from their reaction mixtures, and isolated and purified by techniques well known in the art. For example, separation can be accomplished by precipitation, chromatography (e.g., column), phase separation (extraction) and distillation. The desired product can then be dried and purified by recrystallization.
The following examples illustrate the foregoing invention, although such examples should not be construed as limiting the scope of the invention. Alternative reagents and analagous processes within the scope of the invention will be apparent to those skilled in the art.